HIV/AIDS the disease of our time

HIV/AIDS is a pandemic which over the last 30 years has infected 60 million people and killed around 30 million. At the moment there is no cure for HIV.

HIV or human immunodeficiency virus is a virus that attacks your immune system, using white blood cells to reproduce itself, leaving sufferers vulnerable to infections. AIDS or acquired immunodeficiency syndrome is the illness that occurs when you contract a secondary infection or HIV has destroyed most of your disease fighting cells. HIV is an infectious disease and is transmitted via sexual contact, directly into the blood stream (i.e. by the sharing of unsterilized needles for intravenous drug use) or from mother to baby across the placenta or in breast milk, but not by saliva.

HIV replicates itself within the human body by binding to cells with CD4 (cluster of differentiation 4) receptors, these include T helper cells and macrophages; this replication permanently damages the cells. These are white blood cells which are involved in stimulating the immune response to infections. An important role of CD4+ T helper cells (i.e. those with CD4 receptors) is initiating the action of CD8 cells which are known as killer T cells, these cells bind to infected, damaged or cancerous host cells and destroy them. Normally, people have 1600 CD4+ cells per cubic mm of blood. If HIV is untreated, the CD4 count drops very low (to around 350 cells/mm³), and the body cannot respond as effectively to infection (and so diagnosis of AIDS).

The gp120 proteins on the surface of the virus bind to the CD4 receptor, with the help of a co receptor called CCR5 or CXCR4; it fuses with the host cell and releases its genetic information in the form of RNA, and some enzymes into the host cell. The virus an enzyme called reverse transcriptase turns the RNA into double stranded DNA using the RNA of the host cell. Another enzyme called integrase allows the viral DNA to then integrate with that of the host cell, where it can remain undetected and inactive for many years. The host cell is then used produce the proteins that make up the HIV virus, the virus matures and then can go on to infect more cells of the body.

HIV symptoms and diagnosis

Several weeks after HIV infection, most people experience seroconversion illness, which lasts up to a month, where the immune system attempts to protect the body from the virus. During this time, sufferers may experience fever, fatigue, swollen glands, muscle or joint pain or an unexplained body rash (the latter being particularly helpful in identifying HIV infection). Unfortunately most of these symptoms are indicative of other illnesses such as flu. After the initial symptoms, whilst HIV spreads throughout the body, there are often no further symptoms for about ten years, this is known as asymptomatic HIV infection. As the person often feels healthy, they are able to transmit their infection to others.

Once the virus has destroyed a significant number of CD4 cells, symptomatic HIV develops, along with a range of symptoms such as persistent tiredness, night sweats, weight loss, persistent diarrhoea, blurred vision, white spots on the tongue or mouth, fever, swollen glands, depression and shortness of breath. These symptoms can last for several months. At this point, sufferers are very vulnerable to opportunistic infections and AIDS. Common opportunistic infections include Candidiasis (thrush is a fungal infection of the mouth throat or vagina), Pneumocystis pneumonia (PCP is a fungal infection leading to fatal pneumonia that can occur when CD4+ count is below 200), Cytomegalovirus (CMV is an infection which causes a disease of the retina of the eye and blindness and can occur when CD4+ count is below 50); some cancers (such as Kaposi sarcoma where tumours commonly grow in the skin, mouth or throat and often grow simultaneously in more than one site), herpes, TB and malaria.

Because its early symptoms mimic other illnesses, and it can lie dormant for many years, HIV is difficult to diagnose. Blood spot tests and saliva tests can be used to confirm if someone is HIV positive(i.e. is infected with HIV) though it make take up to three months for the virus to show up as present in the body. It is estimated that currently 24% of HIV sufferers in the UK are unaware of their condition.

HIV treatment

There is no cure for HIV. Recent studies have shown that the average life expectancy for a patient who is receiving treatment that maintains a CD4+ cell count of over 500cells/mm³ is equivalent to someone who does not have the disease. Worldwide, it is estimated that only 28% of HIV sufferers receive the full course of treatment, and often in developing countries (where the disease is more prevalent) there is less protection against opportunistic infections.

Preventing the spread of HIV is important in reducing the deaths due to HIV/AIDS. Although more people have unprotected sex than inject drugs, the risk of contracting H.I.V. is 1 in 125 from an unsterilized syringe, about 1 in 1,200 from unprotected anal sex and 1 in 2,000 from unprotected vaginal sex. In the UK knowingly transmitting HIV to another person is a criminal offence.

Education about the risks of unprotected sex is essential in reducing transmission of HIV. Sex with multiple partners is a large risk factor for contracting HIV, especially with those in the sex industry, encouraging monogamy could help reduce the spread of HIV. Anal, vaginal and oral sex can all transmit HIV, abstinence from these activities provides 100% protection, and male and female condoms can both significantly reduce the risk of transmission. Improving availability of condoms (and lubricants to prevent condoms breaking), encouraging HIV tests and encouraging sexual partners to be honest with one another.

Intravenous drug users should not share syringes or preparation equipment with others, and use sterile syringes and water. Governments and charities have created needle-exchange programs a reliable source of sterilised syringes, and recommend users to be screened for HIV each year. Though obviously the ideal solution would be to stop the use of drugs, as they can affect judgement (i.e. more likely to forget to take medication, engage in unprotected sex or offer paid sex in exchange for drugs), and 50-90% of HIV positive drug users also have Hepatitis C, but due to the nature of addiction this is usually not possible. Heroin users at risk of HIV are offered methadone treatment as the drug can be taken orally; users of other drugs such as methamphetamine are encouraged not to inject.

People living with HIV are encouraged to be routinely vaccinated against opportunistic infections such as flu, to prevent AIDS. They are encouraged to engage in safe sex, not only to prevent the spread of HIV, but to protect themselves against sexually transmitted infections. Maintaining a healthy lifestyle and good hygiene are also important to eliminate infection. These precautions have been successful, as in the UK, death rates due to AIDS are falling. However, this means there are more healthy HIV carriers to spread the disease.

A huge problem with HIV treatment is that most HIV sufferers do not stay on their course of treatment. There are a few side effects of HIV drugs such as nausea, fatigue and diarrhoea and they can worsen mental health conditions such as depression. Recreational drugs such as cocaine also react unpredictably with HIV medication. However, due to improvements in HIV pharmaceuticals, most HIV treatment consists of just one or two pills a day each providing drug combinations, making it easier to remember to take all of the medication required. We need to improve education to ensure that everyone who is able to receive treatment is able to stick with the course.

Anti-retroviral therapy is the current treatment for HIV. It is very effective as not only can it significantly Improve well-being of people with HIV, it can reduce the risk of transmission by 96%. A combination of ARV drugs is used because HIV can quickly adapt and become resistant to one single ARV. If treatment involves three or more different drugs it is known as HAART (highly active anti-retroviral therapy). For the treatment to be effective, it will need to be taken on time, every time. The drugs keep the virus at a low level in the body which allows the person to recover from damage caused by the virus. This treatment must be continued throughout the life of an HIV positive individual, as even if they feel healthy, the virus can be latent within CD4 cells (i.e. has integrated its genetic information with that if its host but has not made new copies).

At the moment, 20 ARV drugs have been approved by the FDA (though not all are available in every country) and these can be classed into 5 groups. NRTIs are nucleotide/nucleoside reverse transcriptase inhibitors, they prevent the action of the reverse transcriptase enzyme, by binding with the enzyme instead of the host nucleotide (the molecules used to make chains of DNA and RNA), so the virus create DNA, so cannot make new copies of itself. NNRTIs have a similar effect, but permanently change the shape of the enzyme, so it can no longer bind to nucleotides. Integrase inhibitors prevent the virus inserting its genetic material into that of the host cell. Protease inhibitors, prevent the virus from making its protein coat or enzymes (which are proteins). Fusion or entry inhibitors prevent the virus binding to a host cell. The latter three ARV drugs are less widely available in developing countries, as they are expensive, particularly protease inhibitors, where a large number of pills need to be taken. Usually treatment includes two NRTIS and an NNRTI or protease inhibitor.

PrEP or Pre-exposure prophylaxis is the use of anti-HIV drugs to reduce the risk of contracting HIV. The first PrEP drug Truvada a daily oral combination tablet has recently been approved by the FDA to help prevent HIV as it reduced infection risk by 73% in a study of heterosexual couples in Africa and 42% amongst homosexual couples. Vaginal gels containing similar drugs have also been trialed in the hope of empowering women whose partners will not wear condoms so that they may be protected. The drugs were found to be effective, yet trials of African females were not particularly successful, mostly due to the lack of adherence to the treatment (with only 21% of under 25s with good adherence to the treatment), so alternatives are being developed that may be more appealing/easier for the use of at risk groups. Drugs are also being trialed amongst injecting drug users. 

PEP, post-exposure prophylaxis, is a month long treatment program with a fairly high success rate that can be administered within the first 72 hours of HIV exposure to prevent infection. The earlier the treatment is started, the more effective it is, but the entire course must be completed and there are some serious side effects of the drugs used.

HIV can be transmitted vertically from mother to baby during pregnancy, during childbirth or by breast feeding. If a HIV positive mother receives no treatment, her baby has a 25% of developing HIV. Mothers can reduce transmission by taking ARV drugs during pregnancy, having caesarean sections, avoiding breastfeeding and ensuring the child receives HIV treatment as a newborn, doing all of these things reduces the risk of transmission to only 2%. In developing countries it is particularly important to provide alternative nourishment for babies born to HIV positive mothers, to prevent transmission via breast milk. Usually babies are treated with a preliminary ARV at birth and tested for HIV from 3 months (so as to be able to differentiate between antibodies produced by the mother and the baby), after which stronger ARVs may be prescribed.

HIV, will there ever be a cure?

So far there has been no luck in finding a permanent cure for HIV sufferers. However, vaccines for the similar virus in chimpanzees, SIV (simian immunodeficiency virus) were successful in that 80% of the rhesus monkeys vaccinated did not contract SIV upon exposure, and those already with SIV were in control of the virus, which over time was no longer found in their bodies. Scientists have had less success in translating these ideas to the human virus, as HIV is very variable, and even weakened forms are dangerous due to the virus’s ability to lie undetected within the body for many years.

Vorinostat is a drug currently used in the treatment of T-cell lymphoma (cancer of the white blood cells). It has been found to have the ability to induce the expression of latent integrated HIV genes (i.e. forcing any cells that are hiding the virus’s genes to produce the virus) This could help in diagnosing patients and in potentially finding a way to ‘flush out’ the virus. There are dangers however, that ‘awakening’ the virus could cause harm to the patient.

In the human body, HIV could produce 100 billion new viruses each day, with each reproduction there are many errors, so great variation between particles, so vaccines are impossible to develop. However, there are several sectors where mutations are very rare so are similar in all forms of the virus. The HIV virus packages its RNA in a specific shape and uses a type of protein called a Gag protein to identify the viral genetic information amongst that of the host. The genetic information for this protein lacks variation, so a potential route for stopping the spread of the virus within the body is to target the RNA that codes for the Gag proteins.

Functionally cured

A baby born in America is thought to have been functionally cured of HIV. The girl who is two-and-a-half years old was born to an HIV positive mother and immediately from birth was treated to a combination of 3 ARVs; she stopped treatment after 18 months, and now appears functionally cured. However, it is unknown whether in this case the baby was born HIV positive.Functionally cured means that a previously HIV positive person no longer needs to take ARV treatment in order to have a healthy immune system, no risk of transmitting the virus and a normal life expectancy (though they may still have traces of the virus in their body). This news, if valid, could be helpful in developing treatments for babies born HIV positive as in Sub-Saharan Africa, 300,000 infants were born HIV positive in 2011. There have also been a group of patients called the Visconti patients, all with HIV infection caught at an early stage (10 weeks), 10% of whom, after 3 years of ARV therapy, have been able to control the virus within their bodies for a decade and appear functionally cured. With both of these cases however, the infection was caught very early, on average people in the UK are diagnosed 5 years after infection.

There has been another high profile case of a cure for HIV, and a potential explanation for the functionally cured baby. In 2007 news broke of an HIV positive man received a bone marrow transplant, and after several months tests no longer showed the presence of the virus. His donor was an ‘super controller’ of the virus, and individual who has a natural resistance to HIV due to a faulty gene for CCR5 co receptors (which allow HIV to bind to CD4+ cells). It is though that 1% of Europeans are super controllers, perhaps due to its ability also to protect from small pox. Tests to disable CCR5 co receptors have so far not had any success, with people treated returning to ARV treatment within 3 months.

Enzymes, proteins which speed up particular metabolic reactions

FDA, the American Food and Drugs Administration are responsible for the approval of new drugs

Macrophages, white blood cells that engulf invading micro-organisms and display the foreign cell markers so that our bodies know which antibodies (which inhibit the micro-organism) to produce.

RNA, a single stranded molecule containing genetic information, unlike double-helical DNA

T helper cells, white blood cells which send out chemical signals to other cells stimulating the production of antibodies and the engulfing of foreign micro-organisms.

http://aids.gov/

http://www.nhs.uk/Conditions/HIV/Pages/Introduction.aspx

http://www.who.int/hiv/en/

http://www.sciencedaily.com/news/health_medicine/hiv_and_aids/

http://www.med.cam.ac.uk/blog/offensive-manoeuvres-in-the-war-against-hiv/

http://www.avert.org/treatment.htm